Polymerizable cyclodextrin derivatives

ABSTRACT

Polymerizable cyclodextrin derivatives (PCDs) are disclosed, wherein each molecule contains at least one covalently attached polymerizable group, may also contain one or more other covalently attached functional ligand group(s), such as free carboxyl group(s), may also contain molecularly encapsulated comonomers, polymerization inhibitors (stabilizers), and polymerization initiators. The groups are attached covalently as ether or ester derivatives in statistically predetermined proportions, in a homogeneous solution, to form a &#34;combinatorial&#34; library having quasi-random molecular configurations of free carboxyl or other ligand groups. In the resulting PCD library, appropriate comonomers and polymerization initiators can be added that will enable timely polymerization to form unique structural adhesives and resins. The adhesive resins can be utilized in preventative and restorative dentistry.

This invention was made in the course of research partially supported bya grant from the National Institute of Dental Research (Grant NumberDE05129-20). The U.S. Government has certain rights in the invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention generally relates to polymerizable monomers that have amultiplicity of functional groups, which compositions are useful ascomponents of dental and industrial formulations for a number ofspecific applications. The principle focus is on functionalizedmethacrylated cyclodextrins, preferably beta-cyclodextrins because ofavailability and economic considerations. However, alpha-andgamma-cyclodextrins and the hydroxyalkylated derivatives of all threefall within the scope of this invention, as do mixtures of these variouskinds of cyclodextrins and their derivatives (CDS), preferably with thestoichiometric equivalence of hydroxyl groups being taken into accountin the preparation of the inventive polymerizable cyclodextrinderivatives ("PCDs").

Although there are reported to be over 10,000 citations regardingcyclodextrins and their derivatives in the literature, it was surprisingto discover in an extensive search that there was apparently nodiscovery or teaching of an art relating to the production and use ofcyclodextrin derivatives in dental materials such as described in thepresent invention. The present invention relates to preparation methodsand utilizations in a spectrum of dental and other uses.

On one end of the spectrum are highly substituted or derivatizedcyclodextrins containing many polymerizable groups, for example,methacrylate and/or acrylate ester moieties, plus or minus otherorganophilic groups to provide organophilic characteristics for use indental sealant resins and dental and other composites. These areexpected to yield formulations with less polymerization shrinkage incomparison to contemporary materials of equal viscosity. The basis forthis is the quasi-spherical configuration of these high-volumecrosslinking monomers together with the prediction of compactness, orhigh density, of monomeric formulations containing comonomers that canfit within the monomeric methacrylated cyclodextrin derivative (MCD) orpolymerizable cyclodextrin derivative (PCD) molecules while liquid, butbecome "external" chain segments during polymerization.

Farther over in this spectrum lie compounds of intermediatehydrophilicity. These compounds comprise derivatives of combinatorialsyntheses of cyclodextrins containing at least one and preferably morethan one polymerizable group on each molecule together with, and also oneach of the same molecules, one and preferably more than one ligandgroup(s) selected from those that can form hydrogen bonds, ionic bondinginteractions, π interactions, hydrophobic bonds, and/or van der Waalsinteractions with corresponding substrate groups.

On the other hand, a minimal number, one or preferably two or more, oforganophilic polymerizable groups, together with a large number ofhydrophilic polar ligand groups can be obtained on molecules in theresulting assortment of compounds for applications such as penetrationand adhesive bonding to appropriate hydrophilic substrates, theformation of dental and other cements, and other medical and industrialapplications. For example, on this end of this spectrum, thesederivatives of cyclodextrin can have a large number of carboxyl ligandgroups and a small number of polymerizable groups for formulations to beused in novel cements, including those resembling dental "glass-ionomercements," zinc oxide-based cements, calcium ion-based cements, andcements comprising admixtures of di- and polyvalent cations withcompounds falling within the scope of this invention.

The combinatorial syntheses of the present invention yield mixtures of(co)polymerizable cyclodextrin derivatives (PCDs). The derived mixtureor "library," of combinations and permutations and the configurations ofthe molecules resulting from syntheses as described herein would, whenproperly formulated with other comonomers and auxiliary components wellknown to the art, and applied to dental surfaces, bind preferentially tosubstrate sites containing some threshold number and/or strength ofinteractions. As the assortment of molecules diffuses into the substratelayers, the particular molecules that find such "docking sites" will beheld in that position while molecules of other configurations willcontinue to diffuse at random through the substrate surface layers untilthey find different surface sites to which they would be strongly bound.Eventually those not finding sites would constitute part of the monomersthat would fill the remaining spaces between the intra-substrate,surface-bound monomers. With appropriate polymerization initiators, bothwould subsequently form a three-dimensional crosslinked polymericnetwork to provide improved bonding between the substrate material andoverlying polymers.

One of the most problematic substrates for dental adhesive bonding isthat of the dentin portion of teeth needing repair. Current techniquesinvolve light acid etching to remove material that is weakly attached tothe dentin or enamel surfaces. This acid treatment also dissolves someof the surface hydroxyapatite and related calcium phosphate minerals,which comprise about one-half of the volume of intact dentin. Thissurface-demineralized layer is then impregnated with monomer solutionsto fill and interact with the resulting collagen-rich surface layer. Themonomers polymerize to form what has become known as a "hybrid layer"comprising interpenetrating synthetic restorative polymers and naturalcollagen polymers.

To date the process has been one of trial and error with specific primercompounds that have a very limited number of configurational groups thatcan interact with the highly diverse sites within the dentin substrate.By contrast the inventive product libraries of multifunctional and multiconfigurational molecules, the PCDs of the present invention, caninteract better by having not only more ligand groups per molecule butalso by having a vast variety of conformations of those ligand groups ondifferent molecules of the "product library" used, which molecules, byautomatic selection, will find and be "recognized" by docking sites. ThePCDs can anchor with multiple interactions to collagen fibrils anddenatured polypeptide portions of the collagen fibrils remaining exposedupon the removal of the previously reinforcing calcium phosphatecrystallites.

Although in most contemporary chemical literature it is assumed that thereaders know the definitions and limits of the terms "combinatorialsynthesis," "combinatorial libraries," and others that are not unrelatedto the present specification, it may be well to define and differentiatesuch as are used herein. "Combinatorial synthesis" herein comprisescombining and reacting a specified amount of one or more cyclodextrincompounds with a specified amount of one or more reagent compounds insuch a way as to produce a mixture of reaction products havingsubstituents located in quasi-random configurations, having variouscombinations and permutations, on one or both of the two rims of thecone-shaped rings of the various cyclodextrin molecules. The term"quasi-random" is used because "random" would imply that all of thepotential reaction sites were equally reactive, which in the case ofcyclodextrins, they are not. The terms "combinatorial libraries,""product libraries," "PCD libraries," or "libraries" as used hereinrefers to the mixture of reaction products resulting from thecombinatorial synthesis just described, either before or afterpurification procedures.

In contrast to conventional combinatorial organic synthetic procedures,which iteratively use combinatorial syntheses to produce combinatoriallibraries together with assays or screening methods to select the onebest compound for a particular purpose from the millions that have beensynthesized, the procedures in the present invention retain most if notsubstantially all of the many heterogeneous monomeric molecules in themixture of reaction products resulting from the combinatorial synthesis.This allows for the large variety of these monomeric PCD configurationsto interact with the large variety of potential docking or anchoringsites that exist in complex substrates, such as, for example, partiallydecalcified dentin, enamel, bone, and many industrial and othermaterials.

Three-dimensional computer modeling of typical portions of type Icollagen the type found in dentin, and a number of typical members ofthe anticipated cyclodextrin derivatives, the "PCD libraries" of thisinvention have indicated that multiple bonding interactions can occurbetween each of the modeled cyclodextrin derivative molecules and themodeled collagen. For example, the PCD's pendant carboxyl groupsinteracted with amino acid side chains such as lysine and arginine,together with hydrogen bonding and "hydrophobic bonding" along thecollagen triple helix. Furthermore, some of the ends of teleopeptidegroups attached to the triple-helical portion of the collagen moleculeand single-chain peptides resulting from ruptured or denatured collagenin the models could fit within the hollow central core of cyclodextrinderivatives of the present invention. Thus, the PCDs may encircle endsof single peptide chains. According to the models, it was surprising tofind that PCD compounds of this invention could also encircle and form"hydrophobic bonds" with the relatively hydrophobic side groups, such asphenylalanine, tyrosine, proline and others, of collagen. In the past,the importance of hydrophobic bonding, in an aqueous environment, in theconfiguring and structural integrity of proteins and of its role in therates of intra- and intermolecular adaptations has been highlyunderrated.

It is also conceived that these multifunctional monomers, as theypenetrate into the surface, can and will form crosslinking bridges withcalcium ions by way of intermolecular carboxyl moieties on thesepolymerizable compounds. Binding to etched enamel should also beexceptionally good by a multiplicity of carboxyl groups interacting withcalcium and multiple H-bonding with phosphate moieties of the highlymineralized enamel surfaces. Individual members within this multifariouscollection of derivatives of cyclodextrin, "PCD library" can range fromhaving one or two to substantially a maximum number polymerizable groupsand a minimum number of polar ligand groups in the formulation ofcomonomers and, optionally, fugitive diluents. This number is notintended to be limiting and can be increased or decreased by alteringthe stoichiometries of the reagents used in the synthesis, depending onthe proposed use and the best results determined empirically.Stoichiometries can be used that yield a distribution having sufficientpolymerizable groups per molecule to provide organophiliccharacteristics and miscibility in comonomers for formulations used asbinders for dental and other composites.

2. Description of the Prior Art

Although there are thousands of references to cyclodextrins and theirderivatives in the general literature, e.g., Takeo et al., 1973; Colsonet al., 1974; Bender and Komiyama, 1978; Saenger, 1984; Szejtli, 1984;Breslow, 1984; Poudrier, 1995, searches to date have revealed neitherreports nor utilization of monomeric methacrylated cyclodextrinderivatives (MCDs) in dental resin formulations, combinatorial syntheticmethods, or libraries, or assemblages of monomeric compounds that havemultiple permutations of polymerizable and adhesion-promoting groupssuch as the polymerizable cyclodextrin derivatives (PCDs) conceived andtaught herein. However, "MCDs" was used to designate methacrylatedcyclodextrins when methacrylate groups were used as the polymerizablemoieties in dental resin formulations (Bowen,1996). Early work by Bowen(1961) showed that certain surface-active comonomers could compete withwater for attachment to hard tooth tissues.

An object of this invention comprises discovering many potentiallyuseful dental applications of appropriately modified cyclodextrins. Oneapplication lies in composites, sealants, cements, and other resinformulations wherein polymerization shrinkage stresses might be reducedwith perhaps less diminution of other desirable physical properties thanby other means alone. As a mechanism, the relatively hydrophobiccavities within (meth)acrylated cyclodextrins house, prior topolymerization, appropriately sized comonomers that have relatively lowdielectric constants, which, during polymerization, may become externalnetwork chain segments. The resulting empty, somewhat rigid cavities(˜42 Å³ per PCD molecule) comprise some of the free volume spaceotherwise lost during polymerization.

The need for monomers that polymerize and crosslink very rapidly,indifferent to the presence of water, with adequate water solubility andvarious surface-activity mechanisms including one based substantially onhydrophobic interactions, comprising partial molecular encapsulation ofsubstrate moieties by components of the applied polymerizable resinadhesive resin, has not been adequately recognized.

Another problem associated with forming complex derivatives of CDS is aneconomical method of forming clearly homogeneous solutions so thatprobability statistics can be applied to form products of the desiredcharacteristics. This requires solvated CD molecules that are not justsuspensions of crystallites or of gelled aggregates when the reagentsare added and mixed at rates lower than reaction rates.

The present conception includes the experimental use of stericallyhindered tertiary alcohols (e.g., t-butyl alcohol) as well as mixturesof appropriate aprotic solvents and amines as solvents to obtain clearand homogeneous solutions of CDS for the syntheses of MCDs and PCDs. Therationale is based on the low S_(N) 2 reactivity of tertiary alcoholscompared with the primary and secondary alcohols of cyclodextrins. Thefeasibility of including hindered tertiary alcohols and the proportionsof reagents to be used when including tertiary alcohols as components inobtaining clear solutions of CDS for combinatorial synthesis reactionsto obtain useful PCDs must be determined empirically, and the mildestand most selective conditions and reagents feasible are recommended.

"Eutectic" mixtures can also be used to lower the melting point andincrease the solubility of CDS in solvents and/or catalysts; in suchcases the stoichiometries and relative reactivity rates must be takeninto account. Eutectic mixtures of the high-melting, and relativelyinsoluble, CDS can utilize the relationship: X=100(T₂ -T_(e))T₁ +T₂-2T_(e), where X is the mole percentage of lower-melting component, T₁is the melting point of the lower-melting component, T₂ is the meltingpoint of the higher-melting component, and T_(e) is the eutectictemperature which is the first sign of melting of the mixture.

U.S. Pat. No. 4,906,488 describes cyclodextrins amongst many "mers" fordelaying the release of "permeants" to outside hosts but does not teachthe use of combinatorial chemistry based on probability statistics toprepare specific diverse but related assemblages or libraries ofsurface-active comonomers for formulations suitable for adhesive andstructural compositions.

U.S. Pat. No. 5,258,414, describes the incorporation of cyclodextrin ora complex of cyclodextrin and blowing agent into a thermoplastic toimprove certain properties but does not disclose formulations or meansto formulate compositions of the present invention.

U.S. Pat. No. 5,268,286, describes a method of immobilizing biocatalyststo various polymers that are unrelated to those of the presentinvention. They include cyclodextrin glucocyltransferase among thebiocatalysts that can be immobilized. Cyclodextrin glucocyltransferaseonly synthesizes cyclodextrins per se! from starch.

U.S. Pat. No. 5,290,831 describes cyclodextrins as stabilizers forpolymerization starters of compositions quite different from thosedescribed herein.

In a preliminary attempt to synthesize MCDs, βCD was dissolved in methylsulfoxide, also known as DMSO, an aprotic solvent in which βCD is quitesoluble. However, during the course of the procedure, it was learnedthat methacryloyl chloride and methacrylic anhydride react with DMSO(Technical Bulletin, 1966), and no product was isolated. This is not inaccord with the assertions of Nussstein et al., U.S. Pat. No. 5,357,012;furthermore, they apparently did not utilize appropriate probabilitystatistics, because an average of "two polymerizable groups percyclodextrin unit" would not assure that each molecule would have evenone such group, which would be necessary to obtain maximum structuralintegrity provided by the present invention. While their products mightbe adequate for the packing of chromatographic columns, they did notteach means to simultaneously provide the adhesion-promoting ligands andmolecularly encapsulated polymerization initiators in monomers suitablefor dental, biological, and other high-performance structural andadhesive compositions disclosed herein.

U.S. Pat. No. 5,362,496 describes the preparation ofnicotine-beta-cyclodextrin complexes.

A restrained, multifunctional reagent described in U.S. Pat. No.5,414,075, is restricted from reacting with either itself or with othermolecules of the same reagent. In its utilization, the reagent requiresthe abstraction of hydrogen atoms by external activation requiring theuse of highly energetic ultraviolet light, which would not be acceptablein dental, medical, and many industrial procedures.

U.S. Pat. No. 5,416,181, includes cyclodextrins in a list ofwater-soluble components to prevent coalescence of water-insolublepolymeric particles in film-forming compositions.

SUMMARY OF THE INVENTION

The novel combination of properties of certain polyfunctional monomersand their formulations provides for an unprecedented variety ofpotential uses in dental, medical and industrial applications where lowpolymerization shrinkage, adhesiveness, and other valuable propertiesare in need of improvement, especially where adhesive bonding to dentinis desired.

For adhesive bonding applications, the quintessential monomers have morethan one carboxyl or other ligand group per monomeric molecule, morethan one methacrylate, acrylate and/or other group that can bepolymerized by a free-radical mechanism, and are controllablyhydrophilic. The carboxyl groups in the monomers or other ingredientscan be used in the form of protonated carboxyl groups, dissociatedcarboxylate groups, salts, amine complexes, esters, amides, and/or otherderivatives. The high crosslink density of these polymers gives greaterstrength, durability, and dimensional stability. Well-cured polymersprepared from these crosslinking monomers have improved dimensional andadhesive characteristics during and after polymerization. This isbecause monomers and formulations described herein can be soluble ormiscible in water and also capable of dissolving water in the monomericformulations. The proportionalities of carboxyl groups and othercomponents determine the desired hydrophilicities for the formulations.When the PCDs are applied in proper diluent formulations, the largevariety of configurations will allow for individual members, which arediscrete compounds of the PCD library of diverse configurations, to bindselectively to their more stable binding sites on the sterically andchemically diverse aspects of the substrate.

An important feature is the amorphous nature of the PCD monomers, whichdistinguishes them from monomers that form crystalline solids. Theviscosities of the monomer formulations can be adjusted to optimumlevels by the use of added comonomers of lower viscosity.

The present invention provides means by which a broad spectrum ofsurface-active, adhesive, crosslinking monomers, which polymerize by afree radical mechanism, can be produced by novel synthesis methods thatare described herein. The inventive conception includes the use ofprobability statistics to obtain new and useful mixtures oforganofunctional PCD monomers. The statistics are used to predeterminethe molar proportions of the synthetic reagents to obtain the desiredproportions of polymerizable, ligand, and hydrophilic groups onindividual members of a very large population of similar but diverse PCDmolecules.

Another object of the present invention is to disclose novel complexesof polymerization photo initiators, which are practicallywater-insoluble, that are molecularly encapsulated (cf. Breslow, 1984)within water-soluble surface-active monomers, which complexes canpenetrate and infiltrate into aqueous substrate environments and adsorbby multiple-bond interactions onto diverse substrates, includingproteins such as collagen, and then, while bound to the surface, besubject to photoinduced reactions that produce free radicals on thesebound complexes, which radicals can then be added onto by double-bondedcarbon vinyl groups, or other groups capable of addition andchain-forming polymerization, for growth outward from these surfaceinitiation sites into the bulk of overlying monomers, which will thenform crosslinked polymers intimately, multiply and densely bonded to thesubstrate surface(s).

It is most advantageous to have surface-bound sources of initiation thatwill allow mobile monomer molecules to approach, add on to, andpolymerize away from a substrate surface. The currently available photoinitiators do not have surface-binding groups and a polymerizable vinylgroup together; therefore, they are not optimal in their capability ofbringing about maximally dense populations of linkages between polymersand substrate surface attachment sites.

Another object of the present invention is to disclose novel complexesof polymerization initiators, for example, benzoyl peroxide orN,N-dimethyl-p-toluidine, which are practically water-insoluble, thatare molecularly encapsulated within the inventive SACs and comonomers,which complexes can penetrate and infiltrate into aqueous substrateenvironments and adsorb on diverse substrate sites.

Another object of the present invention is to provide compositions thatcan reduce polymerization shrinkage and also improve adhesive bonding bycomplying with the following adhesive bonding factors: (1) members ofthe composition should have "chameleonic" solubility characteristics bybeing capable of rearranging intramolecular configurations, with polargroups that can be turned inward or outward relative to organophilicmoieties, to allow solubility in both polar liquids like water andrelatively nonpolar liquids, like acetone, water-insoluble comonomers,etc., to allow diffusion to "anchor" sites; (2) members should havemutual spacial arrangements of hydrophobic groups or areas that fit, inthree dimensions, with complimentary hydrophobic groups or areas on thesubstrate, e.g., collagen fibrils; (3) members should have complimentarycharges (e.g.,--NH⁺ -O₂ C--) relative, in three dimensions, toaccessible regions in the substrate; (4) members should have two or moreanionic, e.g., carboxyl, groups arranged appropriately to allow forbridging by Ca⁺⁺ and/or other divalent or multivalent cations betweenmolecules and with the substrate; (5) members should have structuresthat allow for multiple H-bonding, after approximation by the othermechanisms, to anchor on "recognition" sites; and, (6) members shouldcontain at least two polymerizable groups to allow for the formation ofa "monomolecular (co)polymer."

The inventive methods and products described herein provide for a broadspectrum of surface-active, adhesive, crosslinking monomers andcomonomers, which polymerize by a free radical mechanism, produced bysynthesis methods that utilize catalysts for the syntheses, some ofwhich catalysts may be retained in the synthesis reaction products tofurther serve, at a later time, to aid in the polymerization of thesemonomers to yield improved adhesion qualities and other desirablecharacteristics not hitherto available. ##STR1## In the schematic shownhere, only one example of a preferred configuration is depicted as aprobable member of the millions of combinations and permutations thatare formed during the combinatorial synthesis of novel structures in aβPCD product library. The polymerizable and ligand substituents andnonderivatized hydroxyl groups, 21 in all, are located in quasi-randomconfigurations on the two rims of the cone-shaped ring of sevenconnected dextrose units. PCD molecules may also form inclusioncomplexes by encapsulating other molecules that can fit within thecentral spaces of the cones.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Of the potential uses of modified cyclodextrins in dental applications,uses also lie in adhesive bonding formulations. For example, dentinsurfaces that have been superficially demineralized probably havedisrupted collagen fibrils with regions of denaturation. Ruptures of thecollagen molecules' triple-helical portions would probably presentoligopeptide chains as end groups. Furthermore, at the ends of thetriple-helical portions of intact type I collagen molecules, there arenonhelical teleopeptide chain extensions, which are relativelyhydrophobic (Fietzek and Kuhn, 1976). According to three-dimensionalcomputer scale models, the inside diameters of βCD molecules canaccommodate individual peptide chains. The outer dimensions are roughlythe same as the diameters of collagen triple helixes. The ends ofpeptide chains and the larger, less-polar side groups of collagen'samino-acid segments e.g., phenylalanine, methionine, etc. mighttherefore allow for novel kinds of hydrophobic bonding contributionsfrom appropriately designed PCDs.

For applications requiring high hydrophile/lipophil ratios (and/oradequate water solubility), such as adhesive bonding to dental and otherhydrophilic surfaces, syntheses utilizing appropriate proportions of(meth)acrylic anhydride and/or cyclic anhydrides e.g., succinic,itaconic, maleic, phthalic, tetrabromophthalic, etc. per CD molecule canbe used.

Hydrophilic PCD monomers and formulations described herein can besoluble or miscible in water to an extent between about 1% by weight andinfinite miscibility and capable of dissolving at least about 1% byweight of water in the formulations or can be relatively insoluble inwater as desired, by virtue of the fact that the proportions ofhydrophilic and organophilic groups or components can be predeterminedby the use of probability statistics together with the combinatorialsynthetic methods disclosed herein.

It was discovered that if a large excess of methacrylic anhydride wereused, practically all of the hydroxyl groups of the βCD molecule couldbe esterified by methacrylate groups, yielding products with very lowwater solubility. However, the use of increased proportions of cyclicanhydrides relative to methacrylic anhydride results in increasedhydrophilicity. The addition reaction of cyclic anhydrides with hydroxylgroups of CD molecules results in monoester substituents that retainfree carboxyl groups. These free carboxyl groups provide ligandfunctions with affinity for substrate sites and also allow for a widerange of miscibility with water, polar fugitive solvents, andhydrophilic monomers and formulations containing them. The activity ofwater in formulations can optionally be made approximately equal to thatin biological tissues to promote biocompatibility and enhanced adhesivecharacteristics of polymers prepared from these formulations. One of theprimary conceptions is that probability statistics can be used todetermine in advance the proportions of hydrophilic ligand groups, e.g.,carboxyl groups from the use of cyclic anhydrides, hydrophilic groupsfrom unreacted hydroxyl groups, and organophylic groups, e.g.,methacrylate or other polymerizable moieties to obtain PCDs mostsuitable for a given application. It was also conceived and is hereindisclosed that catalysts, stabilizers, accelerators, chain-transferagents, appropriate organophilic monomers, and polymerization initiatorscan be cornplexed hosted within the molecules of these PCD compounds sothat they will not be separated by partitioning during penetration ofthe monomers into the substrate adherends, an essential feature of theinvention.

The following illustrates how probability statistics can be used. Afirst problem was to determine how few moles of methacrylic anhydride orof other reagents, each molecule of which would attach a polymerizablemonomeric group, M, per mole of βCD could be used and yet have at leastone M group on each βCD product molecule. If in the reaction vesselthere was a solution containing sufficient βCD (e.g.,>10¹⁰ molecules, or>˜10⁻¹³ mole) and if N_(c) represented the number of βCD molecules, withthe simplifying assumptions that each of the 21 hydroxyl groups (K=21)on the βCD molecules were equally reactive and that each M-producingreagent molecule would react with and only with βCD hydroxyl groups,then the question became one of determining the number (N_(m)) ofM-producing reagent molecules to add in order to have at least a 95%)probability that at least 99% of the βCD molecules would acquire one ormore attached polymerizable M group(s). If p denotes the very unlikelyprobability that a given βCD molecule would end up without any Ms, then

    p=(1-N.sub.m /K·N.sub.c).sup.k

because N_(c) and N_(m) are so large. This relationship was based oncombinatorial probability arguments that ##EQU1##

If X denotes the insignificant number of βCD molecules that end upwithout any Ms and X is to be less than 1% of N_(c) and N_(m) is large,it follows that the distribution of X is essentially Poisson, whichdistribution implies that its variance is equal to its mean. And becauseits mean is large (1% of 10¹⁰ is still very large), the Normalapproximation to its distribution could be used. Thus to havePr(X<0.01·N_(c))=0.95, it was necessary to have Pr((X-N_(c) ·p )/(N_(c)·p )⁰.5 <(0.01·N_(c) -N_(c) ·p )/(N_(c) ·p)⁰.5)=0.95 so that (from theNormal distribution) (0.01·N_(c) -N_(c) ·p) /(N_(c) ·p)⁰.5 =1.645. Thesolution of the quadratic equation for p, in view of the size of N_(c),gave

    p=0.01-0.1645/√N.sub.c.

With the equating of these two expressions for p and solving for N_(m),

    N.sub.m =K·N.sub.c (1-0.01.sup.1/k (1-16.45/(K√N.sub.c)))

was obtained. Therefore in this case (where K=21 ), N_(m) /N_(c) ≧4.14.

It should be noted, however, that the 21 hydroxyl groups on βCDmolecules are not all equally reactive: Initially, the 7 primaryhydroxyl groups of C(6) are the most reactive, the 7 secondary hydroxylson the C(2) ring positions are somewhat less reactive, and leastreactive are the 7 secondary hydroxyl groups on the C(3) positions.Steric hindrance also becomes a factor as reagents become attached to agiven βCD molecule. These considerations greatly increase theprobability that each product molecule would have at least onepolymerizable group when the 4.1 4/βCD ratio is used and reacts so as toattach. Impurities and side reactions would obviously have the oppositeeffect. If reagents and reaction conditions are such that only 7hydroxyl groups react, for example the primary hydroxyl groups of theC(6) positions, then N_(m) /N_(c) ≧3.38. If 14 hydroxyl groups react,N_(m) /N_(c) ≧3.93.

To obtain corresponding values for use with alpha-cyclodextrin, 6, 12,or 18 are used for K in the calculations described above. K=8, 16, or 24are used for gamma-cyclodextrin derivatizations.

In order to be even more certain that crosslinking and multifunctionality of ligand groups are possible with every product molecule,it would be desirable to have a minimum of at least two of each kind ofgroups on all molecules of the heterogeneous assembly of combinationsand permutations to be used in the formulations for variousapplications. Accordingly, further statistical probability calculationswere carried out to determine the molar ratio of reagent molecules toβCD molecules that should be used to ensure a high probability, >0.95,that at least 99% of each product molecule, in the libraries of PCDs,would have at least two such groups covalently bonded to it. The resultsof these calculations indicated that 5.8 moles of reagent per mole ofβCD are needed in order to have a probability of 0.95 that at least 99%of the various PCDs' molecules will have more than one reagent groupattached. For example, 5.8 moles of methacrylic anhydride per mole ofβCD, each molecule of βCD having 21 reactive hydroxyl groups, if thereis homogeneous mixing and random reactions with the hydroxyl groups,would yield a family of PCD molecules with an average of 5.8methacrylate ester groups on the PCDs in general and more than onemethacrylate ester group on each of the very small number of PCDmolecules having the least number of methacrylate groups per molecule.Similar reasoning applies to other reagent compounds providing othertypes of polymerizable groups, ligand groups, or other functionalgroups.

On the other hand, to reserve for a special purpose at least oneunreacted site (hydroxyl group on at least 99% of the βCD moleculeswith >0.95 probability), a proportion of 16.86 reagent molecules shouldbe reacted per βCD molecule.

For use in applications wherein the symmetry and structural rigidity ofthe PCD scaffold rings are important, it may be desirable to limit theextent of derivatization of hydroxyl groups so as to conserve hydroxylgroups on the least-reactive C(3) atoms. By this means, intramolecularO(3)--H...O(2')hydrogen bonding can be retained so that themolecules'cores retain much of their potential inflexibility by analogy,relative to methylated cyclodextrins described by Harata (1991).

End use formulations may be prepared from the inventive PCDs describedherein and adjusted to optimum viscosity levels by admixture withmonomers of lower viscosity, water, and/or other miscible fugitivesolvents. Comonomers include but are not limited to methacrylates,acrylates, dimethacrylates and diacrylates, oligomethacrylates andoligoacrylates, styrene, divinylbenzene, and others as may beappropriate for industrial and other uses or applications, withdimethacrylates being preferred.

It is important to utilize formulations with a potential for a highcrosslink density and structural and dimensional stability of theresulting thermoset resin, because of the potential plasticizing effectof water and/or entrapped solvents. Water and/or miscible fugitivesolvents might inadvertently be incorporated within the formulationduring the polymerization, and/or imbibed, sorbed, or otherwiseincorporated from surrounding environments before, during, and/or afterpolymerization occurs in situ. Fugitive solvents are defined herein asthose that are volatile and intended to be fleeting and ephemeral, toassist in the application and penetration of the solutes.

POLYMERIZABLE GROUPS

To prepare the inventive PCDs, an appropriate average number orprobability distribution of polymerizable groups are covalentlyattached. The reagents for this purpose may be of a homogeneous type oran admixture of different types of reagents, provided that they areadequately reactive with the hydroxyl groups of the CDS' scaffold andthat the total number of these reagent molecules complies with theprobability statistics described herein. These reagents includemethacrylic and acrylic acid chlorides and anhydrides, maleic anhydride,itaconic anhydride, glycidyl methacrylate, glycidyl acrylate,2-isocyanatoethylmethacrylate, 2-isocyanatoethylacrylate,2-halo-ethylmethacrylate, 2-halo-ethylacrylate, 4-vinylbenzylchloride orbromide, and other reagents, known to those reasonably skilled in theart of chemistry, that can attach polymerizable groups to hydroxylgroups. The preferred reagents include methacrylic acid chloride,methacrylic anhydride, acrylic anhydride, and glycidyl methacrylate. Theforegoing reagents can provide PCDs having substituents containingmethacrylate, acrylate, vinyl, or other groups capable of free-radicalpolymerization.

It is also desirable to have at least one or more viscosity-controllingcomonomer(s) in formulations comprising PCD compositions. Thesecomonomers can be selected from one or more of the group comprisingtriethylene glycol dimethacrylate; 2-hydroxyethyl methacrylate;cyclohexyl methacrylate; benzyl methacrylate; methyl methacrylate;glycerol dimethacrylate; polyethylene glycol 400 dimethacrylate;polyethylene glycol 600 dimethacrylate; polyethylene glycol 400diacrylate; PEG 1,000 dimethacrylate; polypropylene glycoldimethacrylate; triethylene glycol diacrylate; diethylene glycoldiacrylate; diethylene glycol dimethacrylate; ethylene glycoldiacrylate; ethylene glycol dimethacrylate; water-miscible,low-viscosity liquid dimethacrylates and diacrylates; divinyl reactionproducts of 4,8-bis(hydroxymethyl)tricyclo 5.2.1.0²,6 !decane with oneor more members selected from the group consisting of methacrylicanhydride, methacryloyl chloride, acryloyl chloride, and acrylicanhydride; the divinyl condensation reaction products of1,4-dimethylolcyclohexane with members selected from the groupconsisting of methacrylic anhydride, methacryloyl chloride, acryloylchloride, and/or acrylic anhydride; styrene; divinylbenzene, and othercompatible comonomers. Preferred comonomers include triethylene glycoldimethacrylate; 2-hydroxyethyl methacrylate; cyclohexyl methacrylate;benzyl methacrylate; methyl methacrylate, and glycerol dimethacrylate.

AMINES

Solvation of CDS, catalysis of esterification, etherification, and/orother reactions in the syntheses of PCDs, co-photoinitiation ofpolymerization, and acceleration of decomposition of certain peroxides(e.g., benzoyl peroxide) can be facilitated by one or more aminesselected from the group consisting of ethyl-4-dimethylaminobenzoate,1,8-diazabicyclo 5.4.0!undec-7-ene (DBU), pyridine,4-(dimethylamino)pyridine, hexamethylenetetramine (methenamine),1,4-diazabicyclo 2.2.2!octane (DABCO), quinuclidine, 2-quinuclidinecarboxylic acid, N,N-dimethyl-p-toluidine,N,N-dimethyl-3,5-dimethylaniline, 4-tert-butyl-N,N-dimethylaniline,N,N-dimethylglycine, N-alkylated imidazoles, triphenylamine, othertertiary amines, triphenyl phosphine, and triphenyl antimony.N,N-dimethylaminoethyl methacrylate, N,N-diethylaminoethyl methacrylate,4-vinylpyridine, 2-vinylpyridine, 1-vinylimidazole, N-vinylformamide,1-vinyl-2-pyrrolidinone, and analogous compounds are amines that aremonomers that can copolymerize with the new monomers of the presentinvention and also that would be useful for catalyzing the synthesis ofthe PCD monomers formed and associate with the carboxyl groups of thePCD monomers and may subsequently aid in the polymerization of the PCDformulations by photoinitiation in conjunction with camphorquinoneand/or other cophotoinitiators. A tertiary amine that may simultaneouslyserve as a catalyst for the syntheses of the monomers, prevent prematurepolymerization, and later act synergistically with polymerization photoinitiators is 2,6-Di-tert-butyl-4-(dimethylamino)methylphenol. Preferredamines include 1,8-diazabicyclo 5.4.0!undec-7-ene (DBU) and pyridine.

POROUS SOLIDS

Falling withing within the scope of this invention is the use, in thesynthesis and/or purification of PCDs, of high-surface-area solids thatmay be organic or inorganic, synthetic or natural, acidic or basic, andionic or relatively nonpolar. Such solids may be activated carbon,acidic or basic oxides or hydroxides, calcium phosphates, ionic-exchangeresins, or mineral compositions comprising synthetic, natural, and/oraltered natural minerals. Such minerals may include but not be limitedto brucite, gibbsite, appropriate members of the kaolin-serpentine groupthat comprises kaolinite, dickite, nacrite, hydrated halloysite,chrysotile, antigorite, and lizardite, appropriate members of thepyrophyllite-talc group, appropriate members of the mica group thatcomprises muscovite and phlogopite, smectite, vermiculite, sepiolite,palygorskite, imogolite, allophane, illite, chlorite, montmorillonite,and other porous, expansible, or pillared minerals. Hydroxy polymers ofaluminum, zinc, titanium, and pillared clays with minimal content oftransition elements capable of redox reactions are preferred. Removal ofresidual pyridine, DBU, other amines, or other compounds used in thesolvation of CDS or the synthesis of PCDs, as well as discoloringimpurities, may be facilitated by binding to or ionic exchange with suchresins or minerals.

CYCLIC MONOANHYDRIDES

To obtain acidic and acid-derived ligand groups on the PCDs, the CDS canbe reacted with cyclic monoanhydrides, preferably in the presence oftertiary amines or other catalysts. Cyclic monoanhydrides that can beused include but are not limited to glutaric anhydride, succinicanhydride, maleic anhydride, phthalic anhydride, tetrabromophthalicanhydride, methyl succinic anhydride, itaconic anhydride, diacetyl-1tartaric anhydride, 2-octen-1-ylsuccinic anhydride,hexahydro-4-methylphthalic anhydride, 1,2-cyclohexanedicarboxylicanhydride, 1,4,5,6,7,7-hexachloro-5-norbornene-2,3-dicarboxylicanhydride, 1-cyclopentene-1,2-dicarboxylic anhydride,2,2-dimethylglutaric anhydride, 2,2-dimethylsuccinic anhydride,2,3-dimethylmaleic anhydride, 2-dodecen-1-ylsuccinic anhydride,3,3-dimethylglutaric anhydride, 3,3-tetramethyleneglutaric anhydride,3,4,5,6-tetrahydrophthalic anhydride,3,5-diacetyltetrahydropyran-2,4,6-trione, anhydride,3-ethyl-3-methylglutaric anhydride, 3-methylglutaric anhydride,3-oxabicyclo (3.1.0)hexane-2,4-dione, bromomaleic anhydride,cis-1,2,3,6-tetrahydrophthalic anhydride,cis-1,2-cyclohexanedicarboxylic anhydride,cis-5-norbornene-endo-2,3-dicarboxylic anhydride, cis-aconiticanhydride, citraconic anhydride, dichloromaleic anhydride,endo-bicyclo(2.2.2)oct-5-ene-2,3-dicarboxylic anhydride,exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride, hexafluoroglutaricanhydride, methyl-5-norbornene-2,3-dicarboxylic anhydride,methylsuccinic anhydride, octadecenylsuccinic anhydride,S-acetylmercaptosuccinic anhydride, tetrapropenylsuccinic anhydride,phenylsuccinic anhydride, 1,2,4-benzenetricarboxylic anhydride,1,8-naphthalic anhydride, 2,3-diphenylmaleic anhydride, 2-phenylglutaricanhydride, 2-sulfobenzoic acid cyclic anhydride, 3,6-dichlorophthalicanhydride, 3,6-difluorophthalic anhydride, 3-hydroxyphthalic anhydride,4,5-dichlorophthalic anhydride, 4-bromo-1,8-naphthalic anhydride,4-methylphthalic anhydride, 5-chloroisatoic anhydride, diphenicanhydride, homophthalic anhydride, isatoic anhydride, N-methylisatoicanhydride, phenylmaleic anhydride, tetrachlorophthalic anhydride,tetrafluorophthalic anhydride, and other cyclic monoanhydrides andsubstituted aromatic and aliphatic cyclic monoanhydrides that do notinhibit polymerization or result in discolored or toxic products.Preferred cyclic monoanhydrides include glutaric anhydride, succinicanhydride, and maleic anhydride.

INITIATORS OF POLYMERIZATION

The present conception includes the utilization as complexes, within aswell as external to the βCD and other PCD monomers of the aforementionedcompounds, of free-radical polymerization initiators, so that they willmigrate and penetrate aqueous and hydrophilic environments along withthese monomers or otherwise be favorably affected in their rate ormanner of inducing polymerization. The initiators may be organophilicand fit within the PCDs or have ionizable groups and/or havesurface-active groups or moieties that render them cooperatively orindependently substantive to substrates of interest to yield enhancedadhesive bonding characteristics to the formulations by virtue ofinitiation of polymer chain growth from molecules attached to thesubstrate. There are numerous free-radical polymerization initiatorswell known to those reasonably skilled in the art; a few of theseinclude camphorquinone (2,3-bomanedione); camphorquinone-10-sulfonicacid (synthesis method described by Pande et al., 1980); and peroxides.AIBN (2,2'-azobisisobutyronitrile), its complexes or derivatives, and/orrelated compounds, and/or peroxides that initiate polymerization byheating, etc., may also be used. Preferred free-radical polymerizationinitiators include camphorquinone and peroxides such as benzoylperoxide. These may be used alone or in co-photoinitiating amines,and/or accelerators for the decompositions of the peroxide(s), dependingon the conditions of end uses.

POLYMERIZATION INHIBITORS AND STABILIZERS

One or more polymerization inhibitor or stabilizer must be used duringthe syntheses and storage of the monomers of the present invention:these must be of a nature that their effectiveness will not be lost byinteraction with the reagents. Such inhibitors and stabilizers includebut are not limited to the following: BHT, butylated hydroxy toluene;oxygen; 3,5-di-tert-butyl-4-hydroxyanisole(2,6-di-tert-butyl-4-methoxyphenol);2,6-di-tert-butyl-4-(dimethylamino)methylphenol; and 2,5-di-tert-butylhydroquinone, all of which have sterically hindered phenolic groups thatare not subject to reaction with glycidyl or anhydride groups.Stabilizers are used in very small concentrations, typically 0.001 to 1%by weight of the overall monomer formulation. The preferred inhibitorand stabilizer is BHT, butylated hydroxy toluene used in a concentrationof about 0.1%.

FORMULATION 1

In this formulation, PCDs containing polymerizable groups and alsotertiary amino groups are produced for uses such as primers or adhesivesto metal surfaces and/or other applications wherein amino ligandfunctionalities are desired. In the case of βCD substantially all of the21 reactive hydroxyl groups can be reacted first with reagentscomprising those which attach polymerizable groups, for example,methacrylic anhydride, methacryloyl chloride, acrylic anhydride,acryloyl chloride, glycidyl methacrylate, glycidyl acrylate, and/orother reagents providing electron-poor double bonds; then, per mol ofpurified product, a sum of between 5.8 and 15.2 (preferably about 10)moles of one or more secondary amines selected from the group comprisingimidazole, N-phenylglycine, ring-substituted N-phenylglycine,ring-substituted N-phenylalanine, and other secondary amines, is reactedby adding to some of the double bonds by means of Michael additionreactions. By such a process a composition can be obtained wherein eachmolecule of these cyclodextrin derivatives contains to a highprobability no fewer than two remaining free polymerizable groups permolecule and also contains to a high probability no fewer than onetert-amine substituent per molecule. Preferred secondary amines areselected from one or more of the group consisting of imidazole,N-phenylglycine, substituted N-phenylglycines, N-phenylalanine, ringsubstituted N-phenylalines, N-methyl-p-toluidine, and other secondaryamines.

FORMULATION 2

Formulations are prepared containing PCDs that have not onlypolymerizable groups but also amino groups, for example, products ofFormulation 1, wherein some or all of the amino groups have beenconverted into complexes with boron trifluoride (BF₃). By means such asthis, one or more fluoride-releasing compound(s) is/are incorporated,and the monomers and/or their polymers might provide a slow release offluoride ions as desired, for example, in dental-restorative orcaries-preventive materials.

FORMULATION 3

Acidic cyclodextrin derivatives with or without polymerizable groups canalso be prepared by use of cyclic anhydrides as reagents. For example,to βCD, partially dissolved in diethylmethylamine, can be reacted maleicanhydride or cyclic glutaric anhydride, at least 21 mol per mol of βCD,until dissolution and reactions are complete. Likewise one or more ofthe cyclic monoanhydrides listed above can be used as judged appropriateby one skilled in the art. Volatile solvents and/or catalysts can beremoved by extraction, heat, reduced pressure, and/or other well-knownmeans, and the products may be used in the formulation of cements byadmixture with polyvalent cation compositions.

FORMULATION 4

For heat-curing applications, AIBN 2,2'-azobisisobutyronitrile!, itsanalogs, benzoyl peroxide, t-butyl peroxide, per esters, other peroxidesand/or other compounds, complexes or derivatives that initiatepolymerization by heating or other forms of thermal activation may alsobe used, either as internal molecular complexes or external molecularmixtures with the MCDs or product libraries of PCDs and/or theirformulations.

FORMULATION 5

A clear and homogenous N,N-dimethylformamide solution of βCD isprepared. To increase solubility if necessary, the βCD may be optionallyadmixed with lesser or eutectic amounts of alpha-cyclodextrin,gamma-cyclodextrin, and hydroxyalkylated derivatives of these CDS,provided that the probability statistics are proportionally adjusted toobtain the desired numbers of substituent groups. The βCD solutioncontaining esterification catalysts, etherification catalysts, or bothif appropriate, and a stabilizer, such as BHT butylated hydroxy toluene,against premature polymerization, is rapidly stirred while a sum of atleast about 4.14, or preferably 5.8, up to but not more thanapproximately 16.86 moles per mole of βCD of one or more reagentsproviding polymerizable groups, including but not limited to thoselisted hereinabove under the heading "POLYMERIZABLE GROUPS," is addedslowly. The mixing rate, and diffusion to obtain a homogeneous solution,should exceed the reaction rate(s), and practically anhydrous conditionsshould be maintained throughout. After these reactions are essentiallycomplete, about 4.14 to about 16.86 moles per mole of βCD of one or morereagents providing ligand groups, including but not limited to thoselisted hereinabove under the heading "CYCLIC MONOANHYDRIDES," arelikewise added. After these reactions are essentially complete, theN,N-dimethylformamide, byproducts, and impurities are removed byextractions with volatile solvents. This can be accomplished with theuse of a strong mechanical stirrer and the alternate addition ofsolvents in which the PCD is practically insoluble but in which theN,N-dimethylformamide is miscible, such as toluene, removal of thesupernatant phase, dilution with a PCD solvent such as ethanol,reprecipitation with solvents such as cyclohexane, acetone, and/orether, and removal of the supernatant phase. This cycle can be repeatedas necessary to obtain the desired degree of purity. To the finalethanol solution can be added the appropriate comonomers, stabilizers,polymerization initiators, and other ingredients, some of which maybecome the complexed "guests" in "host" PCD molecules. The ethanol maybe allowed to remain or may be removed by facilitated evaporation.

FORMULATION 6

This combinatorial synthesis is like that of FORMULATION 5 except thatthe reagents providing polymerizable groups and the reagents providingligand groups are mixed together before adding to the CD solution,providing that these reagent groups are compatible and do notunfavorably interact before or after they are added to the CD solution;furthermore, if the reaction rates of these reagents are adequatelysimilar in their reactions with the CD's or CDS'hydroxyl groups, themixed reagents may be gradually added to, react with, and bring intosolution, suspensions of CDS, provided that the proportions are suchthat to a high probability, >0.95, every molecule in the resultingheterogeneous mixture of molecules in the PCDs contains at least onepolymerizable group.

FORMULATION 7

A very large number of novel PCD structures (a "library") is formed by acombinatorial synthesis in which some or all and at least one of thehydroxyl groups of substantially all of the CD molecules are etherifiedby reaction with glycidyl methacrylate and/or glycidyl acrylate and inwhich some or all of the hydroxyl groups thereby generated on the2-hydroxy-3-methacryloxypropyl and/or 2-hydroxy-3-acryloxypropyl ethersubstituents and/or some or all of the unreacted CD hydroxyl groups areesterified by reaction with cyclic anhydride molecules in such a mannerthat substantially all of the PCD molecules have one or preferably morethan one carboxyl group(s). Preferred catalysts for this synthesiscomprise DBU, triphenylamine, triphenyl phosphine, and triphenylantimony.

FORMULATION 8

To each mole of dried β-cyclodextrin, dissolved in sufficientN,N-dimethylformamide to form a clear solution, is added 0.001 to 1mole, preferably 0.01 mole, of 1,8-diazabicyclo 5.4.0!undec-7-ene (DBU),and is added 0.001 to 1 mole, preferably 0.01 mole, of BHT (butylatedhydroxytoluene), all with continued stirring at about ambienttemperature, and is added slowly dropwise about 6 moles of methacrylicanhydride; when esterification is complete, as indicated by any one of anumber of analytical methods known to those skilled in the art ofanalytical chemistry, about 6 moles of cyclic glutaric anhydride,dissolved in N,N-dimethylformamide or an inert volatile solvent, isadded slowly dropwise; when esterification is complete, as indicated byany one of a number of analytical methods known to those skilled in theart of analytical chemistry, the reaction products (herein referred toas a "PCD library" of various molecular-product configurations due todiffering combinations and permutations in the reaction sites on theβ-cyclodextrin molecules) are precipitated by dropwise addition (whilestirring is continued) of toluene, 4-vinyl toluene, and/or other inert,preferably volatile, relatively nonpolar solvent(s) in whichN,N-dimethylformamide, 1,8-diazabicyclo 5.4.0!undec-7-ene (DBU), andmethacrylic acid are soluble or miscible; the supernatant is removed bydecantation or filtration if necessary, and then the precipitated PCDlibrary is diluted to a fluid consistency by admixture with ethanol,methanol, 2-hydroxyethyl methacrylate, and/or other polar and/or proticsolvents that are miscible with both the PCD library and also withsolvents that will precipitate the PCD library, such as those solventsjust described; then, while maintaining as necessary an adequatestabilizer concentration of about 0.001 to 1%, preferably about 0.01 to0.1% by weight relative to the theoretical yield of PCD library productmaterial, this just-described process of precipitation and decantationor filtration is repeated until the unwanted solvents, catalysts, and/orbyproducts are removed from the desired PCD library, as determined byanalytical methods known and available to those skilled in the art. Thederived polymerizable cyclodextrin derivatives ("PCDs") are thenoptionally formulated as desired by adding diluent comonomers,polymerization initiators, and/or other appropriate agents at theappropriate time as indicated for the desired end-use application(s),and packaged in a kit or otherwise for distribution and use. Fallingwithin the scope of this invention are substitutions of optimalsolvents, catalysts, stabilizers and details of procedure by thoseskilled in the relevant arts.

ADDITIONAL EXAMPLES Additional Example 1

Substantially all of the 21 hydroxyl groups of beta-cyclodextrin (βCD)can be esterified to yield monomeric methacrylated beta-cyclodextrins(MβCDs) that are amorphous and soluble or miscible in dental resins andvolatile solvents used in dental applications. Methods for synthesis andpurification are described in the following examples. A residue ofcombinations and permutations of PCDs, polymerizable cyclodextrinderivatives, containing both methacrylate ester groups and hydroxylgroups was presumably obtained from evaporative concentration of thecombined aqueous phases obtained in the purification of the MβCDsdescribed below.

Additional Example 2

A stoichiometric excess of methacrylic anhydride (MAnh) was reacted withdried βCD (F.Wt.˜1135) in pyridine. βCD (73 g as received, courtesy ofAmerican Maize-Products Co., Hammond, Ind., lot E6019-720) was dried ina vacuum oven (about 30 kPa, 108° C., 1 d) to a constant weight of 64 g.From this about 15 g (0.0137 mol; 0.288 OH equivalent) of βCD wascombined with 0.0212 g BHT (butylated hydroxytoluene), 68.9 g ofanhydrous pyridine, and 79.4 g of "94%" methacrylic anhydride (0.484mol). The mixture was magnetically stirred in a closed round-bottomflask that was maintained at temperatures ranging between 28° and 50° C.for five hours, after which the heat was turned off and stirring wascontinued in the closed system at about 22° C. Subsequently, fivedifferent aliquots of the practically clear, very light yellow solutionwere withdrawn, and various methods were evaluated for separating thedesired product(s) from the solvent and by-products. The aliquots werenumbered in the chronological order taken.

Additional Example 3

Aliquot 1 (20 mL) was let down into 250 mL of stirred, 0° C. distilledwater. BHT (butylated hydroxytoluene; 0.0027 g) was added, and stirringwas continued during which time a very viscous cohesive productseparated. The clear aqueous phase was decanted off, and the resin phasewas dissolved in 25 mL of methanol. BHT (0.0054 g) was added to theclear solution, which was then concentrated in a desiccator having apartial vacuum (about 30 kPa) and indicating Drierite (W. A. HammondDrierite Co., Xenia, Ohio). This produced a very viscous clear liquidthat was then heated in an open vessel in a vacuum oven at about 105° C.for 4.5 h, cooled in a vacuum desiccator, and then stored in arefrigerator at about 0° C. This aliquot resulted in about 4.73 grams ofa clear, light yellow glassy solid.

Additional Example 4

Aliquot 2 (20 mL) was filtered overnight by gravity through a Whatman #2paper, yielding a clear light yellow filtrate. The filtrate wasconcentrated in a vacuum oven at about 110° C. for 3 d, yielding 7 gramsof clear dark amber, very viscous liquid. It was then dissolved inmethanol (29 g). To this solution, distilled water was added dropwisewith stirring. Each addition produced "snowflakes" that dissolved inabout 10 s. When 10.9 g of water had been added, the precipitatedsediment appeared cohesive, and the supernatant was decanted off. Theresidue was redissolved by the addition of methanol, and the product wasreprecipitated by the addition of water with vigorous stirring; amilk-white emulsion was produced. This mixture was gravity filtered(Whatman #42), and the filter cake was dried in a vacuum desiccator. Thedry white powdery MβCD recovered (some was lost by spilling) was ≧2.0 g.

Additional Example 5

Aliquot 3 (40 mL) was gravity filtered into a distilled water bathcontaining ice cubes (prepared from distilled water) during which timethe bath was agitated with an ultrasonic generator. After the productphase had settled, the aqueous phase was gravity filtered through aWhatman #2 paper, producing a clear filtrate. The water-insoluble resinphase was air dried, resulting in a slightly off-white solid (11.6grams), which was dissolved in methanol (˜132 g) and filtered. Withvigorous stirring of the filtrate, water (85 g) was added slowly toprecipitate the product, which was separated by filtration. The product,dried in a vacuum desiccator, yielded 7.9 of white MβCD.

Additional Example 6

Aliquot 4 (40 mL) was gravity filtered through a Whatman #2 (medium)filter paper into a flask. The clear light amber filtrate (38.8 grams)was concentrated for 24 h in a rotary evaporator at about 50° C. withvacuum from a mechanical pump. The clear, viscous, amber, concentratedliquid (18 g) was thinned with methanol (˜31 g) and then rapidly stirredwhile water (249 g) was slowly added. The supernatant above theprecipitated material had an apparent pH of about 4, suggesting thatresidual methacrylic acid was present in the solution. The product wasseparated by filtration, redissolved with methanol (˜32 g), precipitatedagain by addition of water (256 g), and separated by filtration. Aftervacuum desiccation, 7.8 g of off-white powder was recovered.

Additional Example 7

Aliquot 5, which was the remainder (29.7 g,˜22 mL), was gravity filteredthrough a Whatman #2 (medium) filter paper into stirred, 65° C.distilled water, from which the product separated as an amber resinphase of relatively low viscosity. After cooling overnight, the resinphase was separated by filtration, "dried" in air (yielding 7.8 g),redissolved in methanol (20 g), and stabilized with additional BHT(0.008 g). Distilled water (393 g) was added slowly with stirring,giving a milk-white suspension of colloidal particles. The nominal pH ofthe suspension was about 6. These particles were collected on a filterand dried in air to yield a solid powdery material (6 g). This was againdissolved in methanol (39 g), filtered, and precipitated by adding water(414 g) with stirring. Gravity filtering overnight and drying with lightvacuum for 10 d yielded a free-flowing, almost white powder (4.9 g).Samples from this aliquot were used for most of the procedures describedbelow. The total MβCD recovered from these 5 trial procedures (˜27.3 g)corresponded to a yield of about 80% of theoretical. The theoreticalformula weight of fully methacrylated beta-cyclodextrin is about 2565.

Elemental analysis of a sample from aliquot 5 indicated the following.Found: C 58.62, H6.37, O 34.88, N not detected (<0.5%, the sensitivityof the method used); the theoretical values were C 59.01, H 6.05, O34.94%. The "missing" 0.13% could represent N from residual pyridineand/or experimental error. Agreement within ±0.40% for C, H, and O iscompatible with a MβCD product having ˜21 methacrylate groups permolecule.

The ¹³ C, ¹ H, and 2-D (2-dimensional heteronuclear correlation of ¹³ Cand ¹ H) NMR spectra also suggest that substantially every one of thehydroxyl groups had been esterified in the "purified,"twice-precipitated, but substantially amorphous, samples of MβCD.Although in appropriate shift positions, the peaks in both proton andcarbon spectra were often not sharp singlets, which broadening could beattributed to a number of causes (Casu et al., 1968).

An estimate of the number of hydroxyl groups on the cyclodextrins thatwere esterified to form methacrylate ester groups was obtained byintegrating the proton nuclear magnetic resonance (¹ H NMR) peaks.Deuterated chloroform, benzene, or methylsulfoxide (DMSO) solutions ofaliquots 2 and 5 provided an isolated peak corresponding to themethacrylate CH₃ groups; however, the two protons on the vinyl sp²carbons gave peaks down field and confounded with the peakscorresponding to the 49 protons located on the 7 dextrose (glucose)rings of the βCD moiety. Therefore, calculations were necessary to"subtract" the vinyl protons from the total protons represented by theoverlapping down-field peaks. The number of methacrylate groups dividedby the number of βCD moieties thereby indicated the average degree ofesterification. About five integrations and calculations were made oneach sample solution, and the values were averaged to accommodateindividual differences in the integrations. The overall average of 30such integrations gave an estimation number of 24 (s.d. 11), which wasslightly above the theoretical 21 methacrylate groups per molecule.

Qualitative solubility tests.

A few granules of the βCD or MβCD were placed on a microscope slide,covered with a cover glass, and examined with a polarizing microscopewhile a drop of liquid was placed to flow under the cover glass. Theseliquids comprised solvents having a wide range of solubility parametersand a number of monomers that might be of interest in dental orindustrial formulations. Subjective solubility ranged from "practicallyinsoluble," wherein the particles showing Brownian motion did notdisappear and the corners of larger ones remained sharp, to "verysoluble," in which cases all particles promptly went into a homogenoussolution. With this method, βCD appeared as birefringent crystals thatwere very slowly and only slightly soluble in water and that werepractically insoluble in methanol and in ethylene glycol dimethyl ether.In contrast, the MβCD particles appeared to be mostly amorphous and werevery rapidly soluble (miscible) in methanol, promptly soluble inhydroxyethyl methacrylate and in benzyl methacrylate, slowly soluble intriethyleneglycol dimethacrylate and in 1,3-glycerol dimethacrylate,very slowly soluble in undiluted BIS-GMA, and practically insoluble inwater.

Photopolymerization of an MCD.

Some of the MβCD product from aliquot 5 (0.2365 g) was dissolved inmethanol (0.9850 g). Camphorquinone (CQ) (0.0152 g) was dissolved inmethanol (0.6141 g). These solutions were combined, giving approximatelya 1:1 CQ to MβCD molar ratio, and allowed to stand for 5 d. The cap ofthe vial was removed to allow slow evaporation of solvent while thesolution was being stirred magnetically. When the clear fluid solutionbecame slightly viscous, a one-drop sample was placed on a microscopeslide and immediately spread under a cover glass, forming a thinsandwiched film. The film was exposed to a dental curing light for 10 sand then checked for cover-glass immobilization with a hand instrument.This exposure to light for 10 s was repeated until the cover glass couldnot be moved. In five replications, one sample "hardened," i.e., thecover glass was immobilized, between 10 and 20 s, three between 20 and30 s, and one between 30 and 40 s.

Thermal interactions of MβCD with benzoyl peroxide (BPO).

According to Fisher-Hirschfelder-Taylor and computer-generated scalemodels, each MβCD molecule can have a central hollow space into which asmaller molecule of appropriate size can fit. Camphorquinone, benzoylperoxide, and N,N-dimethyl-para-toluidine have sizes such that each ofthese could be hosted within MβCD molecules. MβCD was combined andshaken vigorously with BPO in a small vial; the proportions were onemolecule of BPO per molecule of MβCD. Sufficient methanol was added tothe sample to slowly form a clear solution. The methanol was thenallowed to evaporate from the opened vial, while it was rotated slowlyat about a 45 degree angle, to promote the "complexation" of the guestBPO molecules within the host MβCD molecules. After the mixture haddried to a thin glassy film on the inside of the vial, the open vial wasplaced in a desiccator with partial vacuum for further drying. The solidresidue was pulverized with a flat ended glass rod to form a fine whitepowder.

A control material was a physical mixture of the MβCD and BPO powders,in the same proportions, combined and shaken vigorously in an identicalvial. After drying in the desiccator, it was further mixed by stirringand gently triturating with a glass rod.

Aliquots of these powders were then placed in a simultaneousDifferential Thermal Analyzer (DTA)/Thermogravimetric Analyzer (TGA;Harrop model ST-736). Heating rates were 2° or 3° C./min to determinethe time and temperature of BPO thermal decomposition and/or theexothermic opening of the double bonds of the MβCD methacrylate groups.DTA/TGA comparisons of these powers were made with each vs. the otherand each vs. an alumina control powder, the weights being equal to about±0.1 mg. When these powders were heated slowly in the DTA/TGA analyzer,the time and temperature of BPO thermal decomposition and/or theexothermic opening of the double bonds of the MβCD methacrylate groupswere distinctly different. The exotherms of the mixed powders precededthose of the "complexed" combination. These results are in accord withan interpretation that in the methanol solution the BPO had beensubstantially complexed as guests within the host MβCD molecules andthat this complexation had thermally stabilized these BPO moleculesrelative to the particles of crystalline BPO in the mechanical mixtureof the two powders.

Additional Example 8

A combinatorial synthesis was carried out wherein methacrylic anhydrideand cyclic glutaric anhydride were both reacted with a clear solution ofdried βCD (F.Wt.˜1135) in a mixture of pyridine, an aprotic solvent, anda nonaromatic amine catalyst. βCD (167.8 g as received, courtesy ofAmerican Maize-Products Co., Hammond, Indi., lot G 6020-42) was dried ina vacuum oven (about 30 kPa, 110° C., 5 d), cooled and stored in aclosed vacuum desiccator containing indicating Drierite®, yielding 145.6g. A solution of 0.0424 g BHT (butylated hydroxy toluene;2,6-di-tert-butyl-4-methyl-phenol) in 144 g of˜anhydrous pyridine wasmagnetically stirred in a closed round-bottom flask and heated to about55° C. Then 30.0 g (0.0264 mol; 0.555 OH equivalent) of the dried βCDwas added, resulting in an almost-clear, translucent suspension thatpromptly became opaque white and difficult to stir. The suspension wasat least as viscous at 94° C. as it was at 23° C. The addition of 32.0 gof N-methyl-2-pyrrolidone (1-methylpyrrolidinone) did not give apparentsolubility improvement over the same temperature range. However, it wassurprisingly discovered that when 1,8-diazabicyclo 5.4.0!undec-7-ene(DBU) was added (34.0 g, which was probably more than necessary) at 80°C., the suspension immediately became a clear, very light yellowsolution. As it cooled to about 63° C., 25.1 mL of methacrylic anhydride(26.0 g, 6 mol per mol of βCD) was added from a dropping funnel into thestirring solution, the temperature being maintained by a prompt exothermand the dropping rate during the 17 min of addition. Two h later, at 57°C., 19.0 g of glutaric anhydride (6 mol per mol of βCD), dissolved in 30g of chloroform, was added dropwise over a 20 min period with a similarexothermic response. The clear, dark-amber solution that formed appearedto remain the same while it stirred in the closed flask for a number ofdays at about 23° C. This mixture of PCDs was purified by adding toluenedropwise while the mixture was stirred, letting the two phases settle,decanting off the toluene phase, thinning to a fluid consistency by theaddition of anhydrous ethanol, and then repeating this procedure.Numerous one-mL samples were withdrawn, and these aliquots were mixed,in small glass vials equipped with poly(tetrafluoroethylene)-linedscrew-caps, with volatile solvents having a wide range of solubilityparameters to determine solubility characteristics, which assisted infurther purifications as described in "FORMULATION 5." For example, toone of the one-mL samples was added one mL of reagent-grade acetone; themixture was agitated vigorously, let settle into two equilibratedphases, and then the upper acetone-rich phase was removed bydecantation. The lower, product-rich phase was heated to about 105° C.in the open vial in a vacuum oven (about 30 Kpa or 21 in. Hg, gage) forabout 3 h, by which time the product had formed a slightly off-whiteopen-cell solid foam. It was mechanically comminuted to a powder theparticles of which were, when viewed under a polarizing microscope,glassy solids that dissolved immediately when water was added.

The rationale for the proportions of reagents used in the synthesis ofthis particular product library was that on average it would containsufficient carboxyl and residual hydroxyl groups to provide sufficientaffinity with water to allow its components to diffuse through water toaccess substrate surface sites, would comprise a PCD library orcomposition of millions of different combinations and permutations orconfigurations, have at least two polymerizable groups, hydroxyl groups,and carboxyl groups on virtually every molecule, and have the desired"chamelionic" characteristics for versatility and miscibility incomonomers and fugitive solvents to mix homogeneously with appropriateformulations containing them.

It is essential that the disparate classes of compounds or compositionsbe taken together as a whole, for this constitutes a major aspect of theinvention, transcending the novelty of individual chemical compositionsof matter.

REFERENCED PUBLICATIONS

Bender M. L., Komiyama M (1978). Cyclodextrin chemistry. New York:Springer-Verlag, pp. 1-39.

Bowen R. L. (1961). Investigation of the Surfaces of Hard Tooth Tissuesby a Surface Activity Test. In: Proceedings of the Workshop on AdhesiveRestorative Dental Materials. Phillips R., Ryge G., editors. At IndianaUniversity, September 28-29, Spencer, Indiana: Owen Litho Service, pp.177-191.

Bowen R. L. (1996) Synthesis of β-Cyclodextrin Methacrylates forPotential Uses in Dental Resins. J. Dent. Res., Vol 75:347, Abstract No.2640.

Breslow R. (1984). Enzyme models related to inclusion compounds. In:Inclusion compounds, volume 3. Atwood J. L., Davies J. E. D., MacNicolD. D., editors. New York: Academic Press, pp. 484-508.

Casu B., Reggiani M., Gallo G. G., Vigevani A. (1968). Conformation ofO-methylated amylose and cyclodextrins. Tetrahedron, 24:803-821.

Colson P., Jennings H. J., Smith Ian-CP (1974). Composition, sequence,and conformation of polymers and oligomers of glucose as revealed bycarbon-13 nuclear magnetic resonance. JACS 96:25/8081-8086.

Fietzek P. P., Kuhn K. (1976). The primary structure of collagen. In:International review of connective tissue research, volume 7. Hall D.A., Jackson D. S., editors. New York: Academic Press, pp. 28, 29.

Harata K. (1991). Recent advances in the X-ray analysis of cyclodextrincomplexes. In: Inclusion compounds, volume 5. Atwood J. L., Davies J. E.D., MacNicol D. D., editors. New York: Oxford University Press, p. 342.

Poudrier J. K., (1995). Corn meets nanotechnology and they're gettingalong "amaizeingly" well. Today's Chemist at Work, February, pp. 25-30.

Saenger W. (1984). Structural aspects of cyclodextrins and theirinclusion complexes In: Inclusion compounds, volume 2. Atwood J. L.,Davies J. E. D., MacNicol D. D., editors. New York: Academic Press, pp.231-259.

Szejtli J. (1984). Industrial applications of cyclodextrins. In:Inclusion compounds, volume 3. Atwood J. L., Davies J. E. D., MacNicolD. D., editors. New York: Academic Press, pp. 331-351.

Takeo K., Hirose K., Kuge T. (1973). Carbon-13 nuclear magneticresonance spectra of cyclodextrins and its peracetates. ChemistryLetters, published by the Chemical Society of Japan, pp.1233-1236.

Technical Bulletin (1966). Dimethyl sulfoxide. Crown ZellerbachCorporation, Chemical Products Division, Camas, Wash. 98607, p 10.

What is claimed is:
 1. A composition of matter comprising a library thatis a mixture of derivatives of cyclodextrins, selected from the groupconsisting of α-cyclodextrin, β-cyclodextrin, and β-cyclodextrin, inwhich substantially each molecule in the library mixture of derivativescontains, according to predicted probability statistics, at least onecovalently attached polymerizable group and wherein said compositionalso contains at least one stabilizing polymerization inhibitor and atleast one polymerization initiator.
 2. A composition of mattercomprising a library that is a mixture of derivatives of cyclodextrinsselected from the group consisting of alpha-cyclodextrin,beta-cyclodextrin, and gamma-cyclodextrin in which substantially eachmolecule in the library mixture of derivatives contains, according topredicted probability statistics, at least one covalently attachedpolymerizable group and wherein substantially each molecule within thislibrary of polymerizable cyclodextrin derivatives also contains at leastone covalently attached monoester group derived by reaction with atleast one cyclic monoanhydride selected from the group consisting ofglutaric anhydride, succinic anhydride, maleic anhydride, phthalicanhydride, tetrabromophthalic anhydride, methyl succinic anhydride,itaconic anhydride, diacetyl-1 tartaric anhydride, 2-octen-1-ylsuccinicanhydride, hexahydro-4-methylphthalic anhydride,1,2-cyclohexanedicarboxylic anhydride,1,4,5,6,7,7-hexachloro-5-norbornene-2,3-dicarboxylic anhydride,1-cyclopentene-1,2-dicarboxylic anhydride, 2,2-dimethylglutaricanhydride, 2,2-dimethylsuccinic anhydride, 2,3-dimethylmaleic anhydride,2-dodecen-1-ylsuccinic anhydride, 3,3-dimethylglutaric anhydride,3,3-tetramethyleneglutaric anhydride, 3,4,5,6-tetrahydrophthalicanhydride, 3,5-diacetyltetrahydropyran-2,4,6-trione, anhydride,3-ethyl-3-methylglutaric anhydride, 3-methylglutaric anhydride,3-oxabicyclo(3.1.0)hexane-2,4-dione, bromomaleic anhydride,cis-1,2,3,6-tetrahydrophthalic anhydride,cis-1,2-cycloheexanedicarboxylic anhydride,cis-5-norbornene-endo-2,3-dicarboxylic anhydride, cis-aconiticanhydride, citraconic anhydride, dichloromaleic anhydride,endo-bicyclo(2.2.2)oct-5-ene-2,3-dicarboxylic anhydride,exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride, hexafluoroglutaricanhydride, methyl-5-norbornene-2,3-dicarboxylic anhydride,methylsuccinic anhydride, octadecenylsuccinic anhydride,S-acetylmercaptosuccinic anhydride, tetrapropenylsuccinic anhydride,phenylsuccinic anhydride, 1,2,4-benzenetricarboxylic anhydride,1,8-naphthalic anhydride, 2,3-diphenylmaleic anhydride, 2-phenylglutaricanhydride, 2-sulfobenzoic acid cyclic anhydride, 3,6-dichlorophthalicanhydride, 3,6-difluorophthalic anhydride, 3-hydroxyphthalic anhydride,4,5-dichlorophthalic anhydride, 4-bromo-1,8-naphthalic anhydride,4-methylphthalic anhydride, 5-chloroisatoic anhydride, diphenicanhydride, homophthalic anhydride, isatoic anhydride, N-methylisatoicanhydride, phenylmaleic anhydride, tetrachlorophthalic anhydride,tetrafluorophthalic anhydride, and other substituted aromatic andaliphatic cyclic monoanhydrides, and other cyclic monoanhydrides, thatdo not inhibit polymerization or result in discolored or toxic products,to provide monoester substituents that retain pendant carboxyl groupsselected from the group consisting of protonated carboxyl groups,dissociated carboxyl groups, salts, amine complexes, and other carboxylgroup derivatives, and wherein the covalently attached polymerizablesubstituents and said monoesters resulting from reaction with one ormore cyclic monoanhydrides on the various individual molecules withinthis library mixture are located with various quasi-random permutationsand combinations on the various individual molecules of this librarymixture, and wherein said library mixture contains at least onestabilizing polymerization inhibitor.